3TT0

Co-structure of Fibroblast Growth Factor Receptor 1 kinase domain with 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (BGJ398)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase.

Guagnano, V.Furet, P.Spanka, C.Bordas, V.Le Douget, M.Stamm, C.Brueggen, J.Jensen, M.R.Schnell, C.Schmid, H.Wartmann, M.Berghausen, J.Drueckes, P.Zimmerlin, A.Bussiere, D.Murray, J.Graus Porta, D.

(2011) J Med Chem 54: 7066-7083

  • DOI: https://doi.org/10.1021/jm2006222
  • Primary Citation of Related Structures:  
    3TT0

  • PubMed Abstract: 

    A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.


  • Organizational Affiliation

    Novartis Institute for BioMedical Research, CH-4002 Basel, Switzerland. vito.guagnano@novartis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Basic fibroblast growth factor receptor 1
A, B
382Homo sapiensMutation(s): 1 
Gene Names: FGFR1FGFBRFLGFLT2
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P11362 (Homo sapiens)
Explore P11362 
Go to UniProtKB:  P11362
PHAROS:  P11362
GTEx:  ENSG00000077782 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11362
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
07J
Query on 07J

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}pyrimidin-4-yl)-1-methylurea
C26 H31 Cl2 N7 O3
QADPYRIHXKWUSV-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
H [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
I [auth B],
J [auth B],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
07J BindingDB:  3TT0 IC50: min: 0.59, max: 4.9 (nM) from 9 assay(s)
PDBBind:  3TT0 IC50: 0.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 209.11α = 90
b = 50.6β = 107.27
c = 66.9γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHENIXmodel building
PHENIXrefinement
MOSFLMdata reduction
SCALAdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-06-13
    Type: Initial release
  • Version 1.1: 2024-02-28
    Changes: Data collection, Database references, Derived calculations